PLA2G4A promotes right-sided colorectal cancer progression by inducing CD39+γδ Treg polarization

Abstract

γδ T cell is a promising candidate cell in tumor immunotherapy. However, γδ T cells polarized to CD39 + γδ Tregs upon colorectal cancer (CRC) induction and the underlying mechanism remains unclear. Here, we discovered that the frequency of CD39 + γδ Tregs, which positively correlated with poor prognosis, was significantly higher in right-sided CRC (RSCRC) than in the left-sided CRC (LSCRC). Interestingly, CD39 + γδ Tregs from RSCRC showed stronger immunosuppressive phenotype and function than LSCRC. Further, the quantitative mass spectrometry data showed that CD39 + γδ Tregs polarization was related to the abnormal activation of the PLA2G4A/AA metabolic pathway in RSCRC. Using an in vitro co-culture system and an orthotopic murine model of CRC, we proved that the overexpression of Pla2g4a in CT26 cells induced CD39 + γδ Tregs inhibiting the anti-tumor immune response. Finally, we found that the overall survival of the PLA2G4A high group was significantly shortened compared to PLA2G4A low RSCRC, while the survival of LSCRC was on the contrary. Collectively, RSCRC with abnormal PLA2G4A expression educates γδ T cells into CD39 + γδ Tregs to promote tumor progression and metastasis. Our work highlights the interaction between cancer cells and immune cells by distinguishing the primary tumor site and deepens the understanding of tumor microenvironment and immunosuppression.

Prognostic and Predictive Value of BGN in Colon Cancer Outcomes and Response to Immunotherapy

“…Translationally, targeting BGN represents a possible strategy to reorient TAMs toward the antitumor M1 phenotype. Treg cells are another vital group of immunosuppressive cells that mediate immune tolerance, inhibition of Tregs by targeting pivotal molecules could reverse tumor immunosuppression (52)(53)(54). In our present study, BGNmediated immunosuppression may also involve Treg cells, which are functionally categorized into nTregs and iTregs (55).…”

Integrated bioinformatical analysis, machine learning and in vitro experiment-identified m6A subtype, and predictive drug target signatures for diagnosing renal fibrosis

“…The cytoplasmic phospholipase A2-α (cPLA2α) encoded by the PLA2G4A gene acts as an upstream regulator of the eicosanoid signaling pathway by providing intracellular AA ( Bazhan and Khaniani, 2018 ). Studies have shown that the PLA2G4A gene can be used as a biomarker in various diseases such as gastric cancer ( Bazhan and Khaniani, 2018 ), acute myeloid leukemia ( Hassan et al, 2021 ; Lai et al, 2021 ), cholangiocarcinoma ( Sun et al, 2019 ), and colorectal cancer ( Zhan et al, 2021a ). PLA2G4A activates the colorectal cancer microenvironment to produce pro-cytokines IL-17A and adenosine, thereby establishing an effective immunosuppressive microenvironment and promoting immune evasion and tumor metastasis ( Zhan et al, 2021b ).…”

“…Studies have shown that the PLA2G4A gene can be used as a biomarker in various diseases such as gastric cancer ( Bazhan and Khaniani, 2018 ), acute myeloid leukemia ( Hassan et al, 2021 ; Lai et al, 2021 ), cholangiocarcinoma ( Sun et al, 2019 ), and colorectal cancer ( Zhan et al, 2021a ). PLA2G4A activates the colorectal cancer microenvironment to produce pro-cytokines IL-17A and adenosine, thereby establishing an effective immunosuppressive microenvironment and promoting immune evasion and tumor metastasis ( Zhan et al, 2021b ). Trametinib inhibits the cell viability and signaling of organoids to a greater extent by inhibiting the expression of PLA2G4A ( Klotsman et al, 2007 ).…”

Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer

“…CD39 + γδTregs are the predominant Treg subtype in human CRC. They act through adenosine-mediated pathways and have stronger immunosuppressive activity than CD4 + or CD8 + Tregs [ 60 ]. The Myeloid-derived suppressor cells (MDSC) can be attracted by the secretion of cytokines such as IL17A and GM-CSF, thus establishing an immunosuppressive network [ 61 ].…”